An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
| Autor: | Pavel Bobal, Jozef Csöllei, Emilio Angelina, Pavlina Marvanova, Janette Bobalova, Sarah Spiegel, Jan Otevrel, Tomas Gonec, Josef Jampilek, Petr Mokry, Tereza Padrtova, Sergio E. Alvarez, Justo Cobo, Ivan Malík, Alirio Palma, Ricardo D. Enriz, Marcela Cristina Vettorazzi, Lina María Vélez Acosta, Santiago Lima |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular SPHINGOSINE KINASE 1 INHIBITORS Stereochemistry Metabolite SYNTHESIS Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Drug Discovery VIRTUAL SCREENING Azepine Protein Kinase Inhibitors Alkyl Pharmacology chemistry.chemical_classification Virtual screening biology Dose-Response Relationship Drug Molecular Structure BIOASSAYS Otras Ciencias Químicas Organic Chemistry Ciencias Químicas MOLECULAR MODELLING General Medicine Sphingolipid Phosphotransferases (Alcohol Group Acceptor) 030104 developmental biology Enzyme chemistry Sphingosine kinase 1 Molecular targets biology.protein Quantum Theory CIENCIAS NATURALES Y EXACTAS |
| Popis: | Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands. Fil: Vettorazzi, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Angelina, Emilio Luis. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Lima, Santiago. Virginia Commonwealth University. School of Medicine; Estados Unidos Fil: Gonec, Tomas. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Otevrel, Jan. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Marvanova, Pavlina. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Padrtova, Tereza. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Mokry, Petr. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Bobal, Pavel. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Acosta, Lina M.. Universidad Industrial Santander; Colombia Fil: Palma, Alirio. Universidad Industrial Santander; Colombia Fil: Cobo, Justo. Universidad de Jaén; España Fil: Bobalova, Janette. Institute Of Analytical Chemistry Of The Czech Academy Of Sciences; República Checa Fil: Csollei, Jozef. Comenius University; Eslovaquia Fil: Malik, Ivan. Comenius University; Eslovaquia Fil: Alvarez, Sergio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Spiegel, Sarah. Virginia Commonwealth University. School of Medicine; Estados Unidos Fil: Jampilek, Josef. Comenius University; Eslovaquia Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina |
| Databáze: | OpenAIRE |
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